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ATF6α activation in human and preclinical models of hepatocellular carcinoma is significantly associated with an aggressive tumour phenotype characterized by reduced survival, glycolytic reprogramming and local immunosuppression.

Allostery enables proteins to respond to signals but remains difficult to engineer. Here, Southern et al. developed a phage-assisted evolution framework for allosteric protein switches yielding high-performance optogenetic transcription factors.

Analyses of snRNA genes in a French cohort of people with rare disorders, with validation through international collaboration, identify monoallelic and biallelic variants in RNU2-2 as frequent causes of neurodevelopmental disorders with epilepsy.

Neural crest cells differentiate into skeletogenic mesenchyme and neuro-glial lineages, thereby contributing to craniofacial formation. Here, single-cell analysis of cranial neural crest shows that specific rRNA modification and ribosome assembly factors contribute to skeletogenic fate. Their disruption causes craniofacial defects, while high levels in neuroblastoma predict poor survival.

Single-nucleus chromatin and RNA sequencing identifies epigenetic chromatin domains that confer vulnerability to paediatric brain tumours such as ependymomas, providing insight into the development of such tumours despite ‘quiet’ genomes.

An anti-HIV-1 antibody that targets an N332_gp120 glycan-independent V3 epitope, a site of Env vulnerability, can decline viremia in HIV-1-infected humanized mice while overcoming classical V3 escape mutations.

CAR-T cells have been found to be less effective as treatment for solid tumours. Here the authors, utilising B7H3 as an antigen, consider how changes in B7H3 binders lead to functional changes of CAR-T cells and differences in tumour outcomes in humanised mouse tumour models.

In photosynthesis, cytochrome c₆ (Cyt c₆) has been evolutionarily replaced by plastocyanin as the electron donor to Photosystem I (PSI). Here, the authors present the cryo-EM structure Cyt c₆: PSI complex from green algae, revealing both novel and ancestral features of donor:PSI interactions.

PCNA–PAF15 has a key role in determining replisome dynamics during genome replication and protecting against genome instability.

Paternal obesity impacts offspring health, though the underlying mechanisms remain poorly understood. Here, the authors show that male obesity drives adipose mitochondrial dysfunction in F₁ mouse progeny via a let-7-DICER axis, identifying a pathway for intergenerational metabolic inheritance

Thermogenetics enables spatiotemporal control of protein activity using temperature. Now, engineering of a compact, insertable thermoresponsive protein module diversifies the classes of proteins amenable to allosteric thermoregulation.

Czernilofsky et al. identified factors that reprogram stromal cells into an inflammatory, dysfunctional state, leading to the structural disorganization of lymph nodes in B cell lymphoma at single-cell and spatial resolutions.

snoRNAs are synthesized and function in the nucleus, but some of them shuttle into the cytoplasm. This study reveals that the mode of transcription, specifically CPF-CF termination, determines whether the snoRNA is exported.

Pathology-oriented multiplexing (PathoPlex) represents a framework for widespread access to multiplexed imaging and computational image analysis of clinical specimens at a relatively high throughput and subcellular resolution.

Multi-ancestry GWAS meta-analysis identifies risk loci for severe nausea and vomiting of pregnancy. Downstream analyses explore maternal and fetal contributions of these loci and their temporal effects.

Hodgson, Huang, Lang et al. show that TDP-43 limits ribonucleoprotein particle condensation into paraspeckles in a concentration- and polymerization-dependent manner. They also link paraspeckle condensation to stress response and neuroprotection.

Genome-wide analysis shows European dogs existed by 14,200 years ago, were already genetically distinct, received less Neolithic Southwest Asian admixture than humans did and contributed substantially to later European dogs.

Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish CD99L2 as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.

Population-scale WGS reveals genetic determinants of persistent EBV DNA, linking immune regulation—especially antigen processing and MHC class II variation—to EBV persistence and heterogeneous disease associations.

Improved red and green indicators for norepinephrine and their characterization are reported. These indicators allow detection of norepinephrine release in awake behaving mice in dual-color fiber photometry and two-photon imaging applications.

Determining the consequences of acetylation for a protein of interest in cells is a considerable challenge. Using genetic code expansion and p53, this study shows that site-specific incorporation of non-hydrolysable acetyllysine analogues enables functional analysis.

Approved antibody–drug conjugates (ADCs) remain constrained by a limited repertoire of payloads with restricted modes of action. Here, the authors present phosphoramidate-based self-immolative linker units that facilitate stable attachment in serum and traceless drug release in the target cell from aliphatic and aromatic alcohols with various modes of action.

Single-variant and ultrarare variant burden analyses leveraging exome sequencing data from 22 cohorts identify new risk genes for amyotrophic lateral sclerosis and show cumulative effects of several rare variants on disease risk.

Here authors demonstrate that distinct muscarinic receptor types drive coordinated salivary output in the tick Ixodes ricinus. Mapping the underlying circuits reveals functional neural pathways that could be targeted to disrupt tick feeding.

Schober and colleagues show that effector CD8⁺ T cells undergo metabolic shutdown, CD8⁺ central memory T cells are the most metabolically active, and naive-like memory T cells are quiescent during the acute phase of the immune response and represent the dominant population of memory CD8⁺ T cells after yellow fever vaccination in humans.

T-cell–mediated rejection (TCMR) remains a major cause of kidney transplant failure with incompletely understood mechanisms. Here the authors use single-nucleus RNA sequencing, spatial transcriptomics and immunofluorescence to show that injured kidney epithelial cell states associate with poor transplant outcomes after T-cell–mediated rejection.

Targeted ablation of prostaglandin E₂ (PGE₂) signalling in CAR T cells enhances their activity in PGE₂-rich solid tumours, with demonstrations of efficacy in vitro, in mouse xenografts and in patient-derived organotypic tumour spheroids.

Scholl et al. show that PopZ forms filamentous condensates driven by its helical domain and inhibited by its disordered region. Phase-dependent conformations modulate client interactions and disruption of filamentation or condensation impairs cellular function and growth.

Coupling live-cell imaging, machine learning and genomic sequencing, the MAGIC platform enables investigation of the cellular context, mutation rates and triggers of spontaneous chromosomal abnormality formation, shedding light on fundamental determinants of chromosomal instability.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Post-acute infection syndromes often have heterogeneous symptoms that are difficult to interpret. Here, the authors develop a latent trajectory analysis framework designed to categorise complex relationships in longitudinal data into distinct disease phenotypes and analyse transitions between them.

A CRISPR screen reveals that loss of structural components of the SAGA complex derails hematopoiesis by decoupling epigenetic control. This halts stem cell maturation, triggers a pathogenic interferon program and boosts human MDS-L cell growth.

Embryonal tumour with multilayered rosettes (ETMR) is a rare and aggressive paediatric brain tumour. Here, the authors analyse intratumour heterogeneity and the tumour microenvironment in ETMR using single-cell and spatial transcriptomics, in vitro cultures, and a 3D forebrain organoid model, finding important aspects – such as the communication with pericytes – for ETMR development and response to therapy.

Chromatin structure is regulated by chemical modifications of histone proteins, but measuring these at single-cell resolution has been challenging. Here, the authors develop a mass spectrometry-based method to profile histone modifications in individual cells, revealing chromatin heterogeneity and differential co-regulation.

Here, the authors present the cryoEM structure of the sodium-translocating methyltransferase (Mtr) complex from Methanosarcina mazei. Along with providing catalytic insights, they identify MtrI, an unannotated small protein, bound to the Mtr complex in a redox-dependent manner.

A PICALM allele associated with increased risk of late-onset Alzheimer’s disease has a microglial-specific role in lipid droplet accumulation.

Cellular Z-RNAs generated during active virus infections are bona fide ZBP1 ligands, and position ZBP1-activated cell death as a host response to counter viral disruption of the cellular transcriptional machinery.

Nagano et al. identify the third mitotic cohesin complex, STAG3–cohesin, which, with its unique biophysical properties, weakens insulation and rewires regulatory interactions of spermatogonial stem cells, shaping the male germline nucleome.

A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Kallies and colleagues examine the role of the chromatin regulator SATB1 in CD8⁺ T cell differentiation during viral infection and cancer. They show that SATB1 is a negative regulator of exhausted CD8⁺ T cell expansion and effector differentiation.

Tea plant has a highly complex and heterozygous genome, and can produce abundant beneficial metabolites. Here, the authors report the haplotype-resolved genome of cultivar Fuding Dabaicha and reveal structural variations associated with secondary metabolism diversity through QTL and mGWAS analyses.

Cancer patients are at increased risk for severe bacterial infections due to immune dysfunction. Here, the authors show that chronic tumor-derived G-CSF drives NAMPT/NAD-dependent neutrophil dysfunction from the progenitor stage, and that targeting this pathway restores infection control.

Analysis of the longest-lived mammal, the bowhead whale, reveals an improved ability to repair DNA breaks, mediated by high levels of cold-inducible RNA-binding protein.   

The multipass membrane transporter MFSD6 localizes to the plasma membrane and acts as a host entry factor for enterovirus D68 (EV-D68) by binding directly to EV-D68 particles through its extracellular, third loop, offering a potential target to combat infections by this emerging pathogen.

There is still a need for effective HIV vaccines. In this phase I clinical trial, the authors show that an HIV-1 vaccine candidate, ConM SOSIP.v7, is well-tolerated in HIV-negative adults and that it elicits a strain-specific neutralising antibody response that differed between female and male participants.

Spatial transcriptomic analysis of cells in intestinal fistulae of patients with Crohn’s disease reveals the existence of specialized fistula-associated cell states with distinct signalling profiles and extracellular matrix architecture.

Dehingia, Milewska-Puchała and colleagues find a pervasive lncRNA-mediated increase in interactions between CTCF and RNA-binding proteins during embryonic stem cell differentiation. These interactions reinforce chromatin architecture in neural cells.

C-COMPASS is an open-source software designed to predict the spatial cellular distribution of proteins and lipids from cellular organelle profiling using a neural network-based regression model.